A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems

Zhang, Dapeng; Iyer, Lakshminarayan M.; Aravind, L.

Nuclease toxins of the REase fold. The REase fold is a highly versatile fold that accommodates considerable structural diversity and has, not surprisingly, been used as the primary fold from which REases of restriction-modification systems are derived (48, 52) . We also found several proteins with this fold to be encoded by genes that are neighbors of SUKH superfamily genes ( Figure 2 ). These versions were originally identified as a distinct conserved domain of unclear affinities-both PSI-BLAST and HMMER searches failed to identify any relationships with previously known domain. However, we observed that the multiple sequence alignment of this domain showed a characteristic signature of conserved residues of the form GE-D-ExK-Q ( Figure 4B ) that matched the pattern of similar conserved residues in the lambda exonuclease and the RecB family of the REase fold (52, 62) . The predicted secondary structure pattern of these domains also closely matched the REase fold with conserved D and ExK motif falling on a b-hairpin as is typical of the REase fold ( Figure 4B ). These observations induced us to use the alignment of this domain in a profile-profile comparison with the HHpred program, and we recovered a composite profile made of diverse REase fold superfamilies such as the VRR-Nuc, lambda exonuclease, the archaeal Holliday junction resolvase and RecB as the best hits (P = 10 À5 ). This suggested that this family defines a novel group of REase-fold nucleases. Given that the majority of the REase-fold enzymes are DNases, we predict that these toxins are likely to cleave the DNA of the target cells.